Current clinical trials of monoclonal antibodies are emphasizing the use of chimeric mouse/human monoclonal antibodies and other genetically designed probes to eliminate their immunogenicity in man. Our preliminary data with four chimeric mouse/human.monoclonal antibodies demonstrate that they vary greatly in eliciting a human antibody response. This response is from a low immunogenicity (chimeric 17-1A and chimeric mT412), to high immunogenicity (chimeric B72.3) with seven out of 12 patients producing antibody to chimera and two having a striking anamnestic response on second challenge. Chimeric 14.18 appears to have an intermediate degree of immunogenicity. In this proposal we will carry out studies to delineate the antibody specificity of the immune response, examine the V regions of chimeric antibodies for the presence of immunodominant T cell specific epitopes thought to be pivotal in initiating B cell immunity and characterize segmental and topographical antigenic epitopes on murine V regions. These studies will utilize a computer program to predict T cell specific epitopes based on a peptide amphipathic a helix model as well as automated peptide synthesis to generate large numbers of potential antigenic peptides based on the primary sequence of V regions. These studies should provide insight into the molecular mechanisms responsible for the immunogenicity (or lack thereof) of these chimeric mouse/human proteins as well as describe the antigenic sites that are the target of the B cell response. This data may aid in the design of genetically engineered antibodies which will be non-immunogenic and allow repeated administration to patients.